TL-895 + Ruxolitinib for Myelofibrosis

Recruiting in Palo Alto (17 mi)

+18 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Telios Pharma, Inc.

Must be taking: Ruxolitinib

Must not be taking: JAKi, BTK, BMX inhibitors

Disqualifiers: Splenectomy, Splenic irradiation, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests TL-895, a new oral medication, for treating Myelofibrosis, a type of bone marrow cancer. It targets patients who haven't tried certain treatments or didn't respond well to previous medications. TL-895 works by blocking enzymes that help cancer cells grow.

Will I have to stop taking my current medications?

The trial requires participants with a suboptimal response to ruxolitinib to continue taking it at a stable dose before joining the study. The protocol does not specify if other medications need to be stopped.

What data supports the effectiveness of the drug Ruxolitinib in treating myelofibrosis?

Ruxolitinib has been shown to improve symptoms, reduce spleen size, and increase overall survival in patients with myelofibrosis. It is effective in managing disease-related symptoms and has a safety profile consistent with its use as a single agent. ^{1 2 3 4 5}

Is the combination of TL-895 and Ruxolitinib safe for humans?

Ruxolitinib, used for myelofibrosis, has been studied for over a decade and is generally safe, though it can cause anemia (low red blood cell count) and thrombocytopenia (low platelet count). These side effects are usually manageable and rarely lead to stopping treatment. ^{1 4 6 7 8}

What makes the drug TL-895 + Ruxolitinib unique for treating myelofibrosis?

The combination of TL-895 and Ruxolitinib is unique because it involves Ruxolitinib, a potent oral inhibitor of JAK1 and JAK2, which helps reduce spleen size and alleviate symptoms in myelofibrosis by blocking specific pathways involved in the disease. This combination may offer a novel approach by potentially enhancing the effects of Ruxolitinib alone, although further research is needed to confirm its efficacy and safety. ^{1 5 9 10 11}

Research Team

Eligibility Criteria

This trial is for adults with Myelofibrosis (MF) who are either new to JAK inhibitor treatments or haven't responded well to Ruxolitinib. They should have a confirmed MF diagnosis, a spleen enlarged by at least 5 cm or of a certain volume, and be in fair health as judged by their ability to perform daily activities.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My blood, liver, and kidney functions are all within normal ranges.

My condition is classified as high, intermediate-2, or intermediate-1 risk.

Exclusion Criteria

I have had my spleen removed or treated with radiation within the last 24 weeks.

I have never been treated with JAK inhibitors before.

My condition worsened while I was on ruxolitinib.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TL-895 and ruxolitinib in a 28-day cycle, with doses adjusted based on baseline platelet count and pre-study stable dose of ruxolitinib

24 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Ruxolitinib (Tyrosine Kinase Inhibitor)
• TL-895 (Tyrosine Kinase Inhibitor)

Trial Overview The study tests TL-895 combined with Ruxolitinib on two groups: those who've never had JAK inhibitors and those whose condition didn't improve enough with just Ruxolitinib. It aims to see if this combination can better manage symptoms of MF.

Participant Groups

Group I: Phase 2 - Cohort 2 suboptimal response to Ruxolitinib Experimental Treatment 2 Interventions

The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose schedule will be the stable ruxolitinib dose schedule as the subject is currently taking prior to entry into the study.

Group II: Phase 2 - Cohort 1 JAKi treatment-naïve MF Experimental Treatment 2 Interventions

The RP2D of TL-895 as determined in Phase 1b will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle. The dose of ruxolitinib will be based on the subject's baseline platelet count.

Group III: Phase 1b - Dose Level 3 Experimental Treatment 2 Interventions

450 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Group IV: Phase 1b - Dose Level 2 Experimental Treatment 2 Interventions

300 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Group V: Phase 1b - Dose Level 1 Experimental Treatment 2 Interventions

150 mg of TL-895 will be administered orally, twice daily (BID) continuously starting on Day 1 in a 28-day cycle combined with the subject's pre-study stable dose of ruxolitinib.

Who Is Running the Clinical Trial?

Telios Pharma, Inc.

Lead Sponsor

Trials

11

Recruited

1,700+

Findings from Research

Ruxolitinib is a dual inhibitor of JAK1 and JAK2, which are crucial in the development of myelofibrosis (MF), and it has been FDA-approved since November 2011 for treating intermediate or high-risk MF.

The review discusses Ruxolitinib's current role in managing MF and explores its potential future applications in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. Malhotra, H.[2021]

Ruxolitinib, the first JAK2 inhibitor, has significantly improved symptoms, spleen size, and overall survival in patients with myelofibrosis compared to traditional chemotherapy, but about 50% of patients discontinue it after 3 years due to resistance or intolerance.

While second-generation tyrosine kinase inhibitors have been tested for patients who discontinue ruxolitinib, they have not shown significant effects on disease progression, highlighting the need for new treatments that target different pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors. Breccia, M., Assanto, GM., Laganà, A., et al.[2023]

Ruxolitinib, a JAK1/JAK2 inhibitor, significantly improves bone marrow (BM) fibrosis and spleen size in patients with advanced myelofibrosis (MF) over a treatment period of up to 66 months, compared to best available therapy (BAT).

Long-term treatment with ruxolitinib not only stabilizes or improves BM fibrosis but also suggests a potential disease-modifying effect, particularly in patients with advanced fibrosis, as indicated by changes in reticulin fibrosis grade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. Kvasnicka, HM., Thiele, J., Bueso-Ramos, CE., et al.[2023]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

In a study of 53 myelofibrosis patients treated with a combination of hydroxyurea and ruxolitinib, significant reductions in white blood cell and platelet counts were observed after 48 weeks, indicating effective management of myeloproliferation.

The combination therapy also led to a notable decrease in spleen size, with the rate of spleen response increasing from 14% to 45%, while maintaining a safety profile similar to that of ruxolitinib alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. Breccia, M., Luciano, L., Pugliese, N., et al.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

In a study of 219 patients with myelofibrosis, ruxolitinib demonstrated a significant efficacy advantage over the best available therapy, with 28% of patients achieving at least a 35% reduction in spleen volume at 48 weeks, compared to 0% in the control group.

Ruxolitinib not only reduced spleen size but also improved overall quality of life and disease symptoms, with manageable side effects, primarily hematologic issues like thrombocytopenia and anemia, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. Harrison, C., Kiladjian, JJ., Al-Ali, HK., et al.[2022]

Ruxolitinib is a selective oral inhibitor of JAK1 and JAK2 that effectively reduces spleen size and alleviates symptoms in patients with myelofibrosis, showing a 41.9% spleen-volume response rate compared to only 0.7% for placebo in a Phase III trial.

Patients taking ruxolitinib also experienced significant improvements in their overall quality of life and symptom scores, with 45.9% showing a ≥ 50% improvement compared to 5.3% for placebo, although the treatment was associated with thrombocytopenia as a dose-limiting toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Ostojic, A., Vrhovac, R., Verstovsek, S.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, effectively managed dose-dependent cytopenias in patients with intermediate- or high-risk myelofibrosis through dose adjustments, as demonstrated in the COMFORT-I trial with 309 participants.

Titrated doses of ruxolitinib of 10 mg BID or higher led to significant improvements in myelofibrosis-related symptoms and reductions in spleen volume by week 24, indicating its efficacy in treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Verstovsek, S., Gotlib, J., Gupta, V., et al.[2021]

Ruxolitinib is commonly used for managing myelofibrosis symptoms, but many patients experience treatment failure after 2-3 years, highlighting the need for alternative therapies like fedratinib.

Fedratinib has shown efficacy in reducing spleen volume and symptoms in patients with myelofibrosis, and ongoing trials are focused on understanding its long-term effects and managing potential gastrointestinal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. England, JT., Gupta, V.[2022]

References

1. India pubmed.ncbi.nlm.nih.gov

Janus activated kinase inhibition in myelofibrosis. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. [2022]